EP4041707B1 - Verfahren zum reinigen von tris-(3-hydroxybutyrato)-glycerylester - Google Patents

Verfahren zum reinigen von tris-(3-hydroxybutyrato)-glycerylester Download PDF

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EP4041707B1
EP4041707B1 EP20804697.9A EP20804697A EP4041707B1 EP 4041707 B1 EP4041707 B1 EP 4041707B1 EP 20804697 A EP20804697 A EP 20804697A EP 4041707 B1 EP4041707 B1 EP 4041707B1
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formula
compound
aqueous solution
organic solvent
solvent
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EP4041707A1 (de
EP4041707C0 (de
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Virna Lucia Cerne
Gabriele Razzetti
Simone Mantegazza
Roberto Rossi
Philippe CARBONI
Niccolò SANTILLO
Davide BRENNA
Emanuele Attolino
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Dr Schaer SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form

Definitions

  • the present invention is defined in the claims and concerns a method to prepare and purify glyceryl-tris-(3-hydroxybutyrate) ester, which is used in diets that require specific nutritional needs, such as for example the ketogenic diet.
  • Glyceryl-tris-(3-hydroxybutyrate) ester having the following structural formula ( I ): and in particular its enantiomer having all three stereogenic centers in configuration (R) of formula ( Ia ) are used in the ketogenic diet (KD) which is a nutritional approach consisting of a high-fat content and low carbohydrate levels.
  • KD ketogenic diet
  • a diet high in fat but low in carbohydrates leads to ketosis, where the body gains energy from fat in the form of ketone products.
  • This type of diet has been used in the treatment of various diseases, for example in the treatment of infantile refractory epilepsy ( E. van der Louw et al. Eur. J. Paediatr. Neurol. 2016 20, 798-809 ).
  • Patent application WO 95/09144 describes a method to obtain glyceryl-tris-(3-hydroxybutyrate) ester of formula ( I ) which provides a first esterification of the glycerin of formula ( II ) with tert-butyl acetoacetate of formula ( III ) and subsequent hydrogenation of the intermediate of formula (IV) in the presence of Raney nickel as catalyst.
  • Patent application JP.03-083950 describes a method to obtain the optically active compound of formula ( Ia ) by means of a sequence of reactions which provide the initial protection of methyl 3-(R)-hydroxybutyrate of formula ( V ) as THP and subsequent hydrolysis to obtain the acid of formula ( VI ).
  • the carboxylic acid is then activated by treatment with CDI and then esterified with the glycerin of formula ( II ) to obtain the protected intermediate of formula ( VII ).
  • the deprotection reaction by the tetrahydropyranyl protective groups of the compound of formula ( VII ) in an acid environment finally leads to the optically active product of formula ( Ia ) :
  • JP.03-083950 is a long method and leads to the desired product with low yields. Furthermore, the product of formula ( Ia ) is purified by chromatography to obtain the pure compound.
  • Both the compound of formula ( I) and its optically active isomer ( Ia ) at room temperature present as oils, as in all cases known to the person of skill in the art for triglycerides of short-chain fatty acids. Since it is not possible to purify the compounds by crystallization, and since it is desired to avoid silica chromatography on an industrial scale, also the purification of a compound of formula ( I ) and formula ( Ia ) to obtain products having a suitable purity higher than 99% in A% HPLC is very complex, and so far it has not been reported in the literature that such a degree of purity has been achieved with different methods.
  • the invention concerns a method to prepare a compound of formula ( I ) as a single enantiomer or as a mixture of isomers, comprising the hydrogenation reaction of a compound of formula ( IV ) in the presence of a ruthenium-based catalyst.
  • Another purpose of the present invention in a method to purify a compound of formula (I) as defined above comprising:
  • the organic solvent S1 is typically an organic solvent selected from a cyclic or acyclic ether or a non-polar aprotic solvent.
  • the organic solvent S2 is typically an organic solvent selected from a polar aprotic solvent; a chlorinated solvent; an ester; or a linear or branched C 3 -C 7 ketone.
  • the invention concerns a method to prepare a compound of formula (I) as a single enantiomer or as a mixture of isomers, comprising the hydrogenation reaction of a compound of formula (IV) in the presence of a ruthenium-based catalyst.
  • the hydrogenation of a compound of formula (IV) can be carried out by catalytic hydrogenation in the presence of a homogeneous or heterogeneous Ru-based metal catalyst.
  • the metal catalyst When the metal catalyst is heterogeneous, it is preferably deposited on an inert support such as, for example, carbon, barium hydroxide, alumina, calcium carbonate; preferably carbon.
  • an inert support such as, for example, carbon, barium hydroxide, alumina, calcium carbonate; preferably carbon.
  • concentration of the metal on the support can vary between about 1 and 30%, preferably between about 5 and 20%.
  • the hydrogen pressure employed can vary between about 1 bar and about 50 bar, preferably between 2 bar and 40 bar, for example, at 3 bar, 4 bar, 5 bar, 6 bar, 7 bar, 8 bar, 9 bar, 10 bar, 15 bar, 20 bar, 25 bar, 30 bar or 35 bar.
  • the molar quantity of catalyst used is comprised between about 0.1 and 10%, preferably between about 0.5 and 5%.
  • the hydrogenation reaction can be carried out in the presence of an organic solvent selected, for example, from a polar aprotic solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, dimethyl sulfoxide; a cyclic or acyclic ether, typically tetrahydrofuran or dioxane or methyl tert-butyl ether; a chlorinated solvent, typically dichloromethane; a non-polar aprotic solvent, typically toluene or hexane; a polar protic solvent, such as a linear or branched C 1 -C 6 alcohol, in particular methanol, ethanol, isopropanol or butanol; an ester, for example ethyl acetate, isopropyl acetate, butyl acetate; a carboxylic acid, for example acetic acid or propionic acid; or water; or mixtures of two or more of said solvents, preferably 2 or 3.
  • the reaction can be carried out in a C 1 -C 6 alcohol, for example ethanol or isopropanol, in an ester solvent, for example ethyl acetate, or in a mixture of an ester solvent, for example ethyl acetate, and water.
  • a C 1 -C 6 alcohol for example ethanol or isopropanol
  • an ester solvent for example ethyl acetate
  • a mixture of an ester solvent for example ethyl acetate
  • This hydrogenation reaction can be carried out at a temperature comprised between about 0°C and the reflux temperature of the solvent; preferably between about 25°C and the reflux temperature.
  • the hydrogenation reaction of a compound of formula (IV) can also be carried out by means of a hydrogen transfer reaction, using a homogeneous or heterogeneous metal catalyst, for example as defined above, and in the same molar quantity, and a hydrogen donor.
  • a homogeneous or heterogeneous metal catalyst for example as defined above, and in the same molar quantity, and a hydrogen donor.
  • the latter selected for example in the group comprising cyclohexene; cyclohexadiene; methylcyclohexene; limonene; dipentene; mentene; hydrazine; phosphinic acid or its derivatives, for example sodium hypophosphite; indoline; ascorbic acid; formic acid or its sodium or ammonium salts; and secondary alcohols, for example isopropanol.
  • the molar ratio between the hydrogen donor and the compound of formula (IV) can be comprised between about 1.5 and 50, preferably between about 1.5 and 10.
  • the hydrogen transfer reduction reaction can be carried out in the presence of an organic solvent, selected for example from one of the solvents mentioned above.
  • the catalyst is heterogeneous and is more preferably Ru/C.
  • the catalyst is homogeneous and is more preferably a Ruthenium complex with mono or diphosphine ligands well known in the chemistry of enantioselective hydrogenations, for example the homogeneous catalyst Ru((R)-BINAP)Cl 2 .
  • the hydrogenation of a compound of formula (IV) using the homogeneous catalyst Ru((R)-BINAP)Cl 2 allows to obtain a compound of formula (Ia) having all three stereogenic centers in configuration (R).
  • the invention provides an advantageous method to prepare a compound of formula (Ia) as defined here, comprising the hydrogenation reaction of a compound of formula (IV) in the presence of the homogeneous catalyst Ru((R)-BINAP)Cl 2 .
  • a compound of formula (IV) is a known compound and can be obtained for example by esterification reaction of glycerin of formula (II) with tert-butyl acetoacetate of formula (III)
  • both the glyceryl-tris(-3-hydroxybutyrate) ester of formula (I) as well as its enantiomer of formula (Ia) are obtained by evaporation of the solvent as liquids having a purity measured by means of HPLC always higher than 90%, but lower than 99%.
  • the present invention also concerns a method to purify a compound of formula (I) or of formula (Ia) comprising:
  • a solvent S1 is an organic solvent selected, for example, from a cyclic or acyclic ether, typically diethyl ether or methyl tert-butyl ether, typically methyl tert-butyl ether; a non-polar aprotic solvent, typically toluene.
  • a solvent S2 is an organic solvent selected, for example, from a polar aprotic solvent, typically acetonitrile; a chlorinated solvent, typically dichloromethane; an ester, for example ethyl acetate, isopropyl acetate, butyl acetate, preferably ethyl acetate; a linear or branched C 3 -C 7 ketone, for example, methyl ethyl ketone, methyl isobutyl ketone.
  • a polar aprotic solvent typically acetonitrile
  • a chlorinated solvent typically dichloromethane
  • an ester for example ethyl acetate, isopropyl acetate, butyl acetate, preferably ethyl acetate
  • a linear or branched C 3 -C 7 ketone for example, methyl ethyl ketone, methyl isobutyl ketone.
  • the washing with the solvent S1 or the extraction with the solvent S2 of a compound of formula (I) or of formula (Ia) can be carried out at a temperature comprised between about 0°C and about 60°C; preferably between about 25°C and about 60°C, for example at 30°C, at 35°C, at 40°C, at 45°C, at 50°C or at 55°C.
  • the solution of a compound of formula (I) or of formula (Ia) in a solvent S2 can be anhydrated by drying. Drying can be carried out by means of anhydration with a dehydrating agent, for example sodium sulfate (Na 2 SO 4 ), magnesium sulfate (MgSO 4 ) or anhydrous calcium chloride (CaCl 2 ), preferably sodium sulfate (Na 2 SO 4 ).
  • a dehydrating agent for example sodium sulfate (Na 2 SO 4 ), magnesium sulfate (MgSO 4 ) or anhydrous calcium chloride (CaCl 2 ), preferably sodium sulfate (Na 2 SO 4 ).
  • a compound of formula (I) or formula (Ia) as a transparent oil with a purity measured by means of HPLC greater than 99% has never been obtained without the aid of chromatographic purification techniques.
  • the present invention also concerns a method to purify a compound of formula (I) or of formula (Ia) with a purity measured by means of HPLC greater than 99% without the aid of purification techniques of the chromatographic type, for example without proceeding with chromatographic purification on ion exchange resin or normal or inverse stationary phases.
  • the present invention also concerns a compound of formula (I) or formula (Ia), obtained in accordance with the process and purification method object of the present invention, having a content of heavy metals lower than 0.5 ppm.
  • Glycerin 150 g, 1.69 mol
  • tert-butyl acetoacetate 1350 g, 8.55 mol
  • the reaction mixture is then concentrated at a reduced pressure of 200-250 mbar and at an internal temperature of 80-90°C, integrating toluene in portions to the reaction mixture for a total of 1.5 1.
  • a solution of glycerol tris-acetoacetate of formula (IV) (100 g, 0.29 mol) in ethyl acetate (500 ml) and the ruthenium on carbon at 5% with water content approximately 50% (30 g) are loaded into a 1000 ml autoclave at room temperature.
  • the autoclave is inerted with nitrogen and after vacuuming it, it is pressurized with hydrogen at 4.5-5 bar and 1000 rpm of stirring for 6-8 hours.
  • the reaction is monitored by means of HPLC analysis and when the reaction is complete the reactor is inerted and the catalyst is filtered on perlite, washing with ethyl acetate (100 ml).
  • the solution is concentrated to residue at reduced pressure and at a temperature of 30-35°C.
  • the crude is dissolved in water (350 ml), treated with decoloring carbon (2.5 g), left under stirring for 2 hours then filtered on perlite and washed with water (150 ml).
  • Sodium chloride (25 g) and methyl tert-butyl ether (140 ml) are added to the aqueous phase.
  • the two phases are left under vigorous stirring for 30 minutes at a temperature of 45-50°C and are separated, discarding the organic phase.
  • More sodium chloride (50 g) and ethyl acetate (400 ml) are added to the aqueous phase.
  • the phases are left under stirring at 45-50°C for 30 minutes and the phases are separated.
  • the aqueous phase is extracted with further ethyl acetate and the organic phases are reunited, anhydrated on sodium sulfate and concentrated to residue at a reduced pressure at a temperature of 30-35°C.
  • the washing and extraction procedure is repeated 3 times obtaining 72 g of the compound of formula (I) as a colorless oil with HPLC purity (200 nm) at 99.3% in A% and a yield of 71%.
  • a solution of glycerol tris-acetoacetate (150 g, 0.43 mol) and the catalyst Ru((R)-BlNAP)Cl 2 (0.69 g, 0.87 mmol) in ethanol (500 ml) are loaded into a 1000 ml autoclave at room temperature.
  • the autoclave is inerted with nitrogen, heated at 40-45°C and after vacuuming it is pressurized with hydrogen at 35 bar and 1600 rpm for 6-8 hours.
  • the disappearance of the starting product is verified by means of HPLC analysis, the autoclave is unloaded, and the solution is filtered on a perlite and carbon panel.
  • the solution filtered to residue is concentrated at a temperature of 45-50°C and at a reduced pressure.
  • the product is dissolved in water (500 ml) and decoloring carbon (3.75 g) is added, leaving it under vigorous stirring for 2 hours at room temperature.
  • decoloring carbon 3.75 g
  • the crude solution is filtered on a perlite panel washing with water (225 ml) and the aqueous solution is used in the purification step.
  • Example 3 Sodium chloride (36 g) is added to the solution obtained in Example 3, it is heated at the temperature of 45-50°C and the aqueous phase is washed with toluene (2x225 ml) and subsequently with methyl tert-butyl ether (2x200 ml). Sodium chloride (180 g) is added to the aqueous solution and the product is extracted with ethyl acetate (2x200 ml), the reunited organic phases are anhydrated with sodium sulphate, filtered on perlite and concentrated to residue at the temperature of 45-50°C and at reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Claims (10)

  1. Verfahren, um eine Verbindung der Formel (I) zu reinigen,
    Figure imgb0018
     als ein einzelnes Enantiomer oder eine Mischung von Isomeren, umfassend:
    a. eine oder mehr Waschungen einer wässrigen Lösung einer Verbindung der Formel (I) und wobei die wässrige Lösung NaCl von 0% bis 5% m/m, mit einem organischen Lösungsmittel S1, umfasst;
    b. Steigerung der Konzentration von NaCl der wässrigen Lösung einer Verbindung der Formel (I) wie in Punkt a. größer als 5% m/m;
    c. eine oder mehr Extraktionen der wässrigen Lösung einer Verbindung der Formel (I), wie in Punkt b. mit einem organischen Lösungsmittel S2, und
    d. Konzentration der Lösung einer Verbindung der Formel (I) in einem organischen Lösungsmittel S2, um eine Verbindung der Formel (I) zu erhalten,
    und wobei das Lösungsmittel S1 ein organisches Lösungsmittel ist, ausgewählt aus einem zyklischen oder azyklischen Ether oder einem nicht-polaren aprotischem Lösungsmittel, und wobei das Lösungsmittel S2 ein organisches Lösungsmittel ist, ausgewählt aus einem polaren aprotischem Lösungsmittel; einem chlorierten Lösungsmittel; einem Ester; oder ein einem linearen oder verzweigten C3-C7 Keton.
  2. Verfahren wie in Anspruch 1, wobei die Verbindung der Formel (I) eine Verbindung der Formel (Ia) ist,
    Figure imgb0019
  3. Verfahren wie in Ansprüchen von 1 oder 2, wobei die wässrige Lösung wie in Punkt a. NaCl von 1% bis 5% m/m umfasst.
  4. Verfahren wie in Ansprüchen von 1 bis 3, wobei die wässrige Lösung wie in Punkt b. NaCl mindestens 10% m/m umfasst.
  5. Verfahren wie in Anspruch 4, wobei die wässrige Lösung wie in Punkt b. NaCl mindestens 15% m/m umfasst.
  6. Verfahren wie in Ansprüchen von 1 bis 5, wobei das organische Lösungsmittel S1 Diethylether, Methyl-tert-butylether oder Toluol ist.
  7. Verfahren wie in Ansprüchen von 1 bis 6, wobei das organische Lösungsmittel S2 Acetonitril, Dichlormethan, Ethylacetat, Isopropylacetat, Butylacetat, Methylethylketon, oder Methylisobutylketon ist.
  8. Verfahren wie in Ansprüchen von 1 bis 7, wobei keiner der Schritte eine Reinigung mittels Chromatographie umfasst.
  9. Verfahren wie in Ansprüchen von 1 bis 8, wobei das Verfahren den Erhalt der Verbindung der Formel (I) beinhaltet, wobei die Verbindung der Formel (I) mittels eines Verfahrens, das die Hydrierreaktion einer Verbindung der Formel (IV)
    Figure imgb0020
     in Anwesenheit eines Ruthenium-basierten Katalysators umfasst, erhalten wird.
  10. Verfahren wie in Ansprüchen von 1 bis 9, wobei die Verbindung der Formel (I), wie in Anspruch 1 definiert, oder die Verbindung der Formel (Ia), wie in Anspruch 2 definiert, einen Anteil von Schwermetallen von weniger als 0,5 ppm aufweist.
EP20804697.9A 2019-10-10 2020-10-06 Verfahren zum reinigen von tris-(3-hydroxybutyrato)-glycerylester Active EP4041707B1 (de)

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IT102019000018491A IT201900018491A1 (it) 2019-10-10 2019-10-10 Procedimento di purificazione del tris-(3-idrossibutirrato)-gliceril estere
PCT/IT2020/050246 WO2021070209A1 (en) 2019-10-10 2020-10-06 Method to purify tris-(3-hydroxybutyrato)-glyceryl ester

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ES2995469T3 (en) 2021-05-21 2025-02-10 Ioi Oleo Gmbh Process for producing high-grade tricaprylin
CN117412948A (zh) 2021-05-21 2024-01-16 Ioi油脂化学品有限责任公司 生产高级脂肪酸多元醇酯，特别是脂肪酸甘油酯的方法
WO2025196156A1 (en) * 2024-03-20 2025-09-25 Arxada Ag Continuous hydrogenation process of acetoacetate esters
WO2025224319A1 (en) * 2024-04-25 2025-10-30 Arxada Ag Reduction of acetoacetate esters in the presence of amines

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JPH0383950A (ja) 1989-08-28 1991-04-09 Kanegafuchi Chem Ind Co Ltd グリセリド誘導体およびその製造法
US5494649A (en) * 1991-10-03 1996-02-27 Cognis, Inc. Process for removing heavy metals from paint chips
WO1995009144A1 (en) * 1993-09-30 1995-04-06 Eastman Chemical Company Nutritive water soluble glycerol esters of hydroxy butyric acid
WO2014037964A2 (en) * 2012-09-06 2014-03-13 Council Of Scientific And Industrial Research Organocatalytic process for asymmetric synthesis of decanolides
TWI679203B (zh) * 2014-06-11 2019-12-11 美商基利法瑪席特有限責任公司 製備抗病毒化合物之方法
US20180177753A1 (en) * 2016-12-23 2018-06-28 Neuroenergy Ventures, Inc. Glyceryl 3-hydroxybutyrates for migraine symptom management

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WO2021070209A1 (en) 2021-04-15
EP4041707C0 (de) 2025-02-19
IT201900018491A1 (it) 2021-04-10
US20230147401A1 (en) 2023-05-11

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